Leptin is a protein expressed by the ob gene. Leptin is secreted by adipose tissue and appears to be both a satiety factor and a regulator of metabolism (Levin et al., 1996 Proc. Natl Acad. Sci. USA 93:1726-1730). Both the mouse gene and its human homologue have recently been identified and sequenced (Zhang et al., 1994 Nature (London) 372:425-431.)
Mice which are homozygous for the ob gene (ob/ob) are obese, perhaps due to an underexpression of leptin. When ob/ob mice are given daily injections of recombinant protein, their food intake was markedly inhibited and they experienced a reduction in body weight and fat. In lean (i.e. wild-type) mice, daily injections of leptin lead to modest decreases of food intake and body weight. The results for body fat have been contradictory. (Pelleymounter et al., 1995, Science 269:540-543; Halaas et al., 1995 Science 269: 543-546; and Campfield et al., 1995 Science 269:546-549.
Obesity in humans is a major disorder associated with mortality, and may result from a number of causes, and at least some may be due to an insufficient amount of leptin produced. Since leptin is a protein, and vulnerable to breakdown and inactivation by the gastrointestinal system, it cannot be delivered orally. It would be desirable to develop a therapy for leptin delivery for obese patients whose obesity is due, in part to a paucity of leptin.
Some forms of obesity do not appear to be treatable by the administration of leptin. In these cases, it is possible that the problem may be due to an insufficient amount of leptin receptors on the cell surface. Alternatively, the receptors which are present on the cell surface may contain mutations which do not allow them to bind to leptin efficiently or efficiently process the signal generated by the leptin binding. Currently no therapy exists which could augment or replace these receptors.